Diabetes refers to a disease process resulting in abnormal glucose homeostasis that is derived from multiple causative factors and characterized by elevated levels of glucose in the blood (i.e., hyperglycemia). Persistent or uncontrolled hyperglycemia is associated with increased and premature morbidity and mortality. Often abnormal glucose homeostasis is also associated both directly and indirectly with alterations of the lipid, lipoprotein and apolipoprotein metabolism and other metabolic and hemodynamic diseases. Therefore patients with type 2 diabetes mellitus are at especially increased risk of macrovascular and microvascular complications, including coronary heart disease, stroke, peripheral vascular disease, hypertension, nephropathy, neuropathy, and retinopathy. Therefore, therapeutical control of glucose homeostasis, lipid metabolism and hypertension are critically important in the clinical management and treatment of diabetes mellitus.
There are two generally recognized forms of diabetes. In type 1 diabetes, or insulin-dependent diabetes mellitus (IDDM), patients produce little or no insulin, the hormone which regulates glucose utilization. In type 2 diabetes, or noninsulin dependent diabetes mellitus (NIDDM), patients often have plasma insulin levels that are the same or even elevated compared to nondiabetic subjects; however, these patients have developed a resistance to the insulin stimulating effect on glucose and lipid metabolism in the main insulin-sensitive tissues, which are muscle, liver and adipose tissues, and the plasma insulin levels, while elevated, are insufficient to overcome the pronounced insulin resistance.
Insulin resistance is not primarily due to a diminished number of insulin receptors but to a post-insulin receptor binding defect that is not yet understood. This resistance to insulin responsiveness results in insufficient insulin activation of glucose uptake, oxidation and storage in muscle and inadequate insulin repression of lipolysis in adipose tissue and of glucose production and secretion in the liver.
The available treatments for type 2 diabetes have recognized limitations. While physical exercise and reductions in dietary intake of calories will dramatically improve the diabetic condition, compliance with this treatment is very poor because of well-entrenched sedentary lifestyles and excess food consumption, especially of foods containing high amounts of saturated fat. Problems with compliance of various known antidiabetic agents also exist due to a lack of overwhelming patient acceptance of injection as the main mode of delivery.
With type 2 diabetes, increasing the plasma level of insulin by administration of sulfonylureas (e.g. tolbutamide and glipizide) or meglitinide, which stimulate the pancreatic beta-cells to secrete more insulin, and/or by injection of insulin when sulfonylureas or meglitinide become ineffective, can result in insulin concentrations high enough to stimulate the very insulin-resistant tissues. However, dangerously low levels of plasma glucose can result from administration of insulin or insulin secretagogues (sulfonylureas or meglitinide), and an increased level of insulin resistance due to the even higher plasma insulin levels can occur. The biguanides increase insulin sensitivity resulting in some correction of hyperglycemia. However, the two biguanides, phenformin and metformin, can induce lactic acidosis and nausea/diarrhea. Metformin has fewer side effects than phenformin and is often prescribed for the treatment of type 2 diabetes.
Despite these known therapies, there is no generally applicable and consistently effective means of maintaining an essentially normal fluctuation in glucose levels in type 2 diabetes. Additional methods of treating the disease, including alternative therapeutic interventions (e.g., incretin-based therapies, such as GLP-1-receptor agonists and DPP-4 inhibitors) and improved modes of pharmacologic administration (e.g., sublingual, intranasal, intratracheal, inhalation, and oral administration) to improve drug utility and compliance, are still under investigation.
The incretin system—a recognized possible point of intervention for diabetic therapies—includes glucagon-like peptide (GLP-1) and glucose-dependent insulinotropic polypeptide (GIP) (“incretins”), which together play an important role in the regulation of insulin secretion by the pancreas and glucose production by the liver. In addition, the incretins are recognized as playing an important role in maintaining pancreatic β-cell mass and differentiation, preventing β-cell apoptosis, decreased glucagon secretion, deceleration of gastric emptying, and promotion of early satiety leading to weight loss.
Normal glucose levels in the blood are, in part, regulated by a balance of the actions of insulin (causes a reduction in blood glucose) and glucagon (signals liver to produce glucose). The balanced action between these two hormones is maintained in a normal individual through pancreatic β-cell production of insulin and glucagon in response to plasma glucose levels. The incretins provide an additional layer of regulation on glucose levels which is triggered at the time of food ingestion. GLP-1 and GIP are released from cells of the intestine upon food intake, which stimulate insulin secretion via GLP-1-receptors and GIP receptors on precreatic cells, and in the case of GLP-1, also which inhibits glucagon secretion from the pancreas, thereby decreasing glucose production by the liver and lowering blood glucose levels overall.
In type 2 diabetes, however, incretin system is greatly diminished. Specifically, the insulinotropic and glucagon-reducing effects of GLP-1 and GIP are impaired in individuals with type 2 diabetes. This recognition led to the recent development of incretin-based therapies, including GLP-1-receptor agonists, such as liraglutide and others, and incretin mimetics, such as exenatide, which interact with the GLP-1 receptor and other receptors of the incretin system to promote insulin release and block glucagon secretion, thereby lowering the overall plasma glucose level. See Gutniak, M., et al. N. Engl. J. Bled. 1992; 326:1316-1322; Grossman, S., “Differentiating incretin therapies based on structure, activity, and metabolism: Focus on Liraglutide,” Pharmacotherapy, 2009; 29(12):25S-32S.
One incretin-based therapy under development includes the GLP-1-receptor agonist and GLP-1 analog, glucagon-like insulinotropic peptide (GLIP), which is a fragment of GLP-1. Gutniak et al., 1992. In normal subjects, the infusion of GLIP significantly lowered the meal-related increases in blood glucose concentration, and the plasma concentrations of insulin and glucagon. In patients with NIDDM, the treatment reduced the requirement for insulin by 8 fold. In patients with IDDM, the GLIP treatment lowered the insulin required by one half. This glucose-dependent activity is a very desirable characteristic for a therapeutic agent that can be used to treat type 2 diabetes while avoiding complications of hypoglycemic side effects.
A more recently developed incretin-based therapy for treating type 2 diabetes is exenatide, which was approved by the Federal Food and Drug Administration (FDA) as a subcutaneous injection (under the skin) of the abdomen, thigh, or arm, 30 to 60 minutes before the first and last meal of the day. Exenatide—a synthetic version of exendin-4, a hormone found in the saliva of the Gila monster that was first isolated by Dr. John Eng in 1992 (Eng, J. et al., J. Biol. Chem. 267:742-7405 (1992)) and described in U.S. Pat. No. 5,424,286 to Eng displays human glucagon-like peptide-1 (GLP-1) activities, functioning as a regulator of glucose metabolism and as an insulinotropic agent (i.e., increases insulin release) through its agonistic action at the GLP-1-receptor.
According to the FDA package insert, exenatide enhances glucose-dependent insulin secretion by the pancreatic β-cells, suppresses inappropriately elevated glucagon secretion, and slows gastric emptying, although the mechanism of action is still under study. Exenatide is a 39-amino-acid peptide and an insulin secretagogue with glucoregulatory effects which binds and activates the pancreatic GLP-1 receptor (GLP-1R) with similar affinity and potency as GLP-1 and thereby promotes insulin secretion and blocks glucagon secretion in a glucose-dependent manner. The effects of exenatide also reportedly include slowing of gastric emptying to modulate nutrient absorption, reduction of food intake and body weight and increased pancreatic β-cell mass and function. In addition, it is inherently a poor substrate for degradation by dipeptidyl peptidase-IV (DPP-IV)—the normal degradative enzyme responsible for removal of the incretins (GLP-1 and GIP). Exenatide was approved by the FDA on Apr. 28, 2005 for patients whose diabetes was not well-controlled on other oral antibiabetic agents (e.g. metformin, sulfonylureas, thiazolidinediones).
Exenatide raises insulin levels quickly (within about ten minutes of administration) with the insulin levels subsiding substantially over the next hour or two. A dose taken after meals has a much smaller effect on blood sugar than one taken beforehand. The effects on blood sugar diminish after 6-8 hours. The medicine is available in two doses: 5 mcg and 10 mcg. Treatment often begins with the 5 mcg dosage, which is increased if adverse effects are not significant.
Two important limitations on the use of exenatide and other incretin-based polypeptide antidiabetic therapeutics potentially include (1) relatively short half-lives upon administration (e.g., exenatide's 2.5 hour half life when delivered by the approved intravenous route) due to proteolytic degradation and (2) lack of effective, but less invasive (and thereby more patient compliant), alternative administration routes (e.g., orally, sublingually, or intranasally) that provide for sufficient bioavailability (Gedulin et al., “Pharmacokinetics and pharmacodynamics of exenatide following alternative routes of administration,” Int'l J Pharmaceuticals, 356 (2008) 231-238).
Accordingly, the development of optimized incretin-based or other insulinotropic polypeptide therapeutics, such as, optimized exenatide, that are imparted with superior stability, protease resistance, and pharmacologic properties, as well as the development of such therapeutics that can be delivered successfully (i.e., achieving improved bioavailability, gastrointestinal absorption and pharmacologic properties) by alternative, more patient compliant delivery routes (e.g., orally deliverable form of exenatide) would be significant advances in the art.